Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and affects a considerable proportion of the general population. NAFLD is independently associated with increased risk for cardiovascular events, particularly coronary heart disease. Importantly, even though NAFLD is more prevalent in patients with major cardiovascular risk factors (e.g., type 2 diabetes mellitus, obesity and hypertension), the association between NAFLD and cardiovascular disease appears to be independent of these risk factors. However, NAFLD also appears to increase the risk for ischemic stroke, a leading cause of mortality and long-term disability worldwide. It also appears that nonalcoholic steatohepatitis is more strongly related to the risk of ischemic stroke than isolated hepatic steatosis. Moreover, emerging data suggest that patients with NAFLD experience more severe ischemic stroke and have more unfavorable prognosis after an acute ischemic stroke in terms of functional dependency and short- and long-term mortality. These associations have major public health implications, since ischemic stroke is the second leading cause of death worldwide and an important cause of long-term disability. The aim of the present review is to summarize the current knowledge regarding the relationship between NAFLD and ischemic stroke incidence, severity and outcome. Given these associations, it might be useful to evaluate patients with acute ischemic stroke for the presence of NAFLD and to manage those with NAFLD more aggressively.

Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease, affects approximately 25% of the general population and is the leading cause of abnormal liver function tests[1,2]. Moreover, the prevalence of NAFLD is even higher in elderly subjects and in patients with type 2 diabetes mellitus (T2DM), obesity, hypertension and/or metabolic syndrome[2,3]. Nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, is present in up to 10% of adults[4]. NAFLD can progress to cirrhosis, hepatocellular cancer or liver failure, and is a major cause of liver transplantation[3,5].

Several studies showed that NAFLD is a risk factor for cardiovascular disease (CVD)[6,7]. Importantly, even though NAFLD is more prevalent in patients with major cardiovascular risk factors (e.g., T2DM, obesity and hypertension), the association between NAFLD and CVD appears to be independent of these risk factors (Figure 1)[6,7].

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Figure 1 Mechanisms underpinning the association between nonalcoholic fatty liver disease and ischemic stroke (broken line suggests the independent association between nonalcoholic fatty liver disease and ischemic stroke).

In this context, accumulating data suggest that NAFLD is also associated with increased incidence of ischemic stroke. Moreover, emerging evidence suggests that NAFLD might also be related with more severe stroke and with worse outcome of patients with acute ischemic stroke. These associations have major public health implications, since ischemic stroke is the second leading cause of death worldwide and an important cause of long-term disability[8,9]. The aim of the present review is to summarize the current knowledge regarding the relationship between NAFLD and ischemic stroke incidence, severity and outcome.

Several studies reported that elevated aminotransferase and g-glutamyltransferase (gGT) levels, which are mostly due to NAFLD, are associated with increased incidence of ischemic stroke (Table 1). In a small case-control study in 103 patients with acute ischemic stroke and 200 controls, alanine or aspartate aminotransferase levels were independently associated with increased odds ratio for ischemic stroke[10]. In a larger prospective study in 6997 men without established CVD or T2DM, gGT levels, a more specific marker of NAFLD, was independently associated with higher risk of ischemic stroke, even in subjects at low- or moderate cardiovascular risk[11]. In EUROSTROKE, a nested-case control study performed in 3 European countries (Finland, Netherlands and United Kingdom), the association between gGT levels and ischemic stroke risk appeared to be stronger in patients without T2DM[12]. Importantly, gGT appears to play a role in atherogenesis[13]. Indeed, gGT has been isolated from atheromatic plaques, macrophages and foam cells[14] and appears to contribute to atherosclerosis by inducing oxidative stress[15]. It was shown than gGT promotes oxidization of low-density lipoprotein and that it plays a crucial role in the catabolism of glutathione and the release of reactive oxygen species[16,17]. In a recent cross-sectional study, NAFLD diagnosed with ultrasonography was associated with increased prevalence of lacunar infarcts in non-obese subjects but not in obese patients[18]. In contrast, in another recent case-cohort study in 572 patients with incident ischemic stroke and 1017 controls, NAFLD defined as fatty liver index > 60 was associated with lower risk in men but there was no association in women[19]. In a meta-analysis of 9 case-control and cohort studies, NAFLD was independently associated with 2.3 times higher risk for ischemic stroke (95%CI: 1.84-2.93)[20]. The strength of this association was comparable in Caucasian and Asian patients[20]. Importantly, this association was independent of traditional cardiovascular risk factors, including dyslipidemia, obesity and T2DM[20].

It appears that NASH is more strongly related to the risk of ischemic stroke than isolated hepatic steatosis. Indeed, in a case-control study in 295 patients with acute ischemic stroke and 1942 subjects who underwent a health check-up, the degree of liver fibrosis, evaluated with transient elastography, was independently associated with increased stroke risk[21]. In contrast, isolated steatosis was not related with the risk of stroke[21].

There are very few data regarding the impact of NAFLD on the severity and outcome of ischemic stroke (Table 1). In an early prospective study in 200 patients admitted with acute ischemic stroke, NAFLD (defined as elevated aminotransferase levels in the absence of other causes) was present in 42.5% of patients[22]. Patients with NAFLD had more severe stroke at admission and worse functional outcome at discharge[22]. However, patients with NAFLD were more obese, had higher prevalence of T2DM and had higher low-density lip–oprotein cholesterol and triglyceride levels than patients without NAFLD; these differences were not adjusted for in the comparisons of stroke severity and outcome between the 2 groups[22]. In a more recent retrospective study in 306 patients with brainstem infarction, a similar prevalence of NAFLD (defined as elevated aminotransferase levels in the absence of other causes) was reported (42.5%)[23]. Patients with NAFLD had more severe stroke at admission and higher risk for neurological deterioration during hospitalization, independently of other risk factors[23]. In contrast, in a prospective study in 415 consecutive patients with acute ischemic stroke, stroke severity at admission, functional outcome at discharge and in-hospital mortality did not differ between patients with NAFLD (defined as elevated aminotransferase levels without another apparent cause) and those without NAFLD after adjustment for other cardiovascular risk factors[24]. However, only 32 patients (7.7% of the study population) had NAFLD[24]. Therefore, this study might have lacked the power to identify an association between NAFLD and stroke severity and outcome[24].

Accumulating data suggest that NAFLD is independently associated with increased risk for ischemic stroke. Moreover, it appears that patients with NAFLD experience more severe stroke and have more adverse functional outcome than patients without NAFLD. Therefore, it might be useful to evaluate patients with acute ischemic stroke for the presence of NAFLD and to manage those with NAFLD more aggressively. It remains to be established whether management of NAFLD will also reduce the risk and improve the outcome of ischemic stroke.